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BIOM30002 - M2M > Lecture 23 - Parkinson's Disease > Flashcards

Lecture 23 - Parkinson's Disease Flashcards

1
Q

What are the clinical symptoms of Parkinson’s disease?

A 
1. Motor
 • Slowness
 • Stiffness
 • Tremor
 • Postural instability
 • Stooped, shuffling gait
 • Decreased arm swing when walking
 • Swallowing difficulty
 • Immobile facial expressions
2. Cognitive
 • Mood changes
 • Depression
 • Anxiety
 • Pain
 • Tiredness
 • Confusion
3. Sensory
 • Numbness
 • Aching
 • Pain
 • Anosmia
  1. Autonomic
    • Hot/cold sensations
    • Constipation
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2
Q

What is lost in PD?

A

Substantia nigra dopaminergic neurons in midbrain

Specifically:
• Ventrolateral area of SN
• i.e. the part where the neurons that extend to the striatum are

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3
Q

At what point does PD present?

A

60-70% of SN dopamineragic cells are lost

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4
Q

What is the function of the SN?

A
  • Control of voluntary movement

* Production of dopamine

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5
Q

What is the function of dopamine?

A
  • Regulation of mood

* Planning and modulation of movement

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6
Q

Where is the SN?

A

In the midbrain

Part of the basal ganglia

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7
Q

What are the basal ganglia?

What is it made up of?

A 
Collection of nuclei in the white matter of the cerebral cortex
Made up of nuclei:
 • Striatum: 
- Putamen
- Caudate nucleus
 • Globus pallidus
 • SN:
- Pars reticulate
- Pars compacta
• Subthalamic nuclei
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8
Q

What are the two parts of the SN?

Which is affected in PD?

A

Pars compacta
Pars reticulata

Pars compacta is made up of the large pigmented neurons that project to the striatum
These are the neurons that are affected

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9
Q

Describe the connectivity of the SN

A

Dopaminergic neurons project to striatum

Release dopamine onto these neurons → control of movement

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10
Q

What causes PD?

A 
1. Sporadic / idiopathic
 • the majority
Suggested mediators:
 • Toxins (such as pesticides)
 • Metals
 • certain drugs e.g. MPTP, a recreational drug
2. Familial
Number of genes identified:
 • α-synuclein (SNCA)
 • Parkin
 • Leucine rich repeat kinase
 • DJ-I
 • PINK1
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11
Q

What pathological features are typical of PD?

A

Lewy bodies:
• Intracellular inclusions of protein

Lewy neurites
• similar to Lewy bodies

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12
Q

What is the composition of Lewy bodies?

A

α-synuclein

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13
Q

What is important about the structure of α-synuclein?

A

Natively unfolded

Basic domain:
• Rich in basic amino acids
α-helical formation

TM domain:
• Hydrophobic region

Acidic domain:
• mainly negatively charged

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14
Q

What is the function of α-synuclein?

A 
Linked to:
 • Learning
 • Development
 • Synaptic plasticity
 • Regulation of vesicular transport & dopamine release
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15
Q

When does Lewy body accumulation start?

A

Proposed that it is well before diagnosis
Normally starts to accumulate outside the SN
Only diagnosed once accumulating in the SN

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16
Q

Which factors modulate the aggregation of α-synuclein?

i.e., what promotes and what inhibits aggregation?

A 
Promotion:
 • α-syn over-expression
 • mutation in α-syn
 • Fe
 • Oxidants
 • Environmental toxins

Inhibition:
• Dopamine

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17
Q

What is the role of α-synuclein and metals?

A

Metals can promote the aggregation of α-synuclein

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18
Q

What is the interaction between α-synuclein and dopamine?

A

Dopamine induce α-synuclein oligomers are not Thioflavin T reactive

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19
Q

Describe the α-synuclein aggregation pathways with and without dopamine

A
  1. W/o dopamine:
    α-syn monomer → α-syn oligomer → insoluble α-syn fibrils (ThT positive) → Lewy bodies
  2. W/ dopamine:
    α-syn monomer → soluble α-syn oligomers (ThT negative)
20
Q

What is the inheritance of α-synuclein mutation?

A

Dominantly inherited

21
Q

What happens in α-synuclein mutation?

Describe how this could lead to disease

A

Copy number variation: duplication & triplication of the gene
→ Over-expression of α-synuclein

Increased α-synuclein concentration promotes aggregation

22
Q

What mouse models have been used to study PD?

A
  1. Mutant human α-synuclein
  2. Over-expression of wild type α-synuclein
  3. Intracerebral α-syuclein inoculation
23
Q

What is observed in mice with mutant human α-synuclein?

What is the significance of this?

A

• Lewy bodies in brain
• Motor deficit
→ Substantiates the theory that α-synuclein causes motor deficits in PD in humans

24
Q

What is observed in mice with over-expression of wild type α-synuclein?

A
  • Lewy body formation
  • Reduced striatal tyrosine hydroxylase levels (→ decreased dopamine)
  • Movement disorder: less time spent on rotorod
25
Q

Describe the propagation of α-synuclein observed in mice studies

What is the significance of this?

A

When α-synuclein is inoculated intracerebrally, there is rapid, progressive neurodegeneration observed

This study was done in mice

Mutant α-synuclein from symptomatic mouse injected into non-symptomatic mouse:
• Reduced life span
• Spreading of α-synuclein from area of injection to other regions

→ Indicated that α-synuclein spreads and propagates throughout the brain once present in PD
This may be what is seen in the Braak staging

26
Q

Describe the cellular release and uptake of α-synuclein

A
  • Through secretory vesicles
  • Multi-vesicular bodies → released in exosomes
  • Recycling endosome: release contents out into extracellular space

The neurons are not dying, but rather are viable

One neurone can deposit α-synuclein into the extracellular space (monomeric or aggregated) and it can be taken up by other cells
e.g.
• Astrocytes take it up → inflammation
• Taken up by other neighbouring neurons → propagation

27
Q

Is Parkin mutation a significant cause of Parkinsonism?

A

2nd most common genetic cause of Parkinsonism

28
Q

What is the function of Parkin?

What is the proposed role in PD?

What type of mutation is it: loss / gain of function ?

A

• Cytosolic protein
• Role in clearance of protein:
- cellular ubiquitination / protein degradation pathway
• i.e. it acts as ubiquitin ligase

Role in PD
 • Loss of Parkin
 • Non-ubiquitinated substrates accumulating in neurons
 • Altered protein turn-over
→ SN degeneration

• Autosomal recessive, loss of function mutations

29
Q

What is the function of PINK1?

What is the proposed role in PD?

A

Normal function:
• Phosphorylation of TRAP1
• TRAP1 is a mitochondrial chaperone protein

Increased phosphorylation of TRAP1 under oxidative stress

In PD:
• Mutations leads to loss of kinase activity

30
Q 
Compare the inheritance of the following:
 • SNCA
 • Parkin
 • PINK1
 • LRRK2
 • DJ-1
A

SNCA: Autosomal dominant

Parkin: Autosomal-recessive

PINK1: Autosomal recessive

LRRK2: Autosomal dominant

DJ-1: Autosomal recessive

31
Q

What is the function of LRRK2?

What is the proposed role in PD?

A

Precise function unknown
• Role in intracellular signalling? (its kinase domain is of the MAPKKK class)
• Promotion of mitochondrial & golgi fragmentation

PD:
• Mutation → Increased kinase activity
• Increased mitochondrial and golgi fragmentation

32
Q

What is the function of DJ-1?

What is the proposed role in PD?

A

Function:
• Unknown
• Involved in modulating the oxidative stress response and mitochondrial function
• Oxidative stress → DJ-1 translocated to outer mitochondrial membrane

In PD:
• Unknown

33
Q

Describe the causal spectrum of PD

A

Familial ←————→ Sporadic
Genetic variants ←–→ Environment

The more dominant the genetic variant, the less role the environmental needs to play

34
Q

Describe the interaction of the mitochondria and α-synuclein

A

α-synuclein interacts with and inhibits Complex I of ETC
→ fragmentation
→ neuronal death

PINK1, DJ-1 and Parkin all interact with the mitochondria
Mutation in the genes for these proteins can lead to mitochondria dysfunction
→ Energy loss from cell
→ Cell death

35
Q

Is the presence of Lewy bodies diagnostic for PD?

A

No

36
Q

What is Braak staging?

A

Stages of PD based on where the Lewy bodies are deposited
6 stages

Location of Lewy bodies:
Stage 1: in dorsal motor nucleus of vagal nerve
→ olfactory structures

Stage 2: Lower raphe nuclei
→ stress and panic responses

Stage 3: SN
→ clinical diagnosis

Stage 4: temporal mesocortex
→ memory and emotions

Stage 5: temporal neocortex
→ memory and language

Stage 6: Neocortex
→ primary sensory areas

Progressive deposition of Lewy bodies
Location of deposition relates to the clinical features seen at that time

37
Q

What is the significance of Thioflavin T reactive material?

A

Signifies aggregation of α-synuclein into amyloid plaques

38
Q

What is the effect of dopamine on pre-formed, insoluble α-synuclein fibrils?

A

Can reverse the aggregation and make it soluble

39
Q

What is the effect of point mutation in the gene for α-synuclein?

A

Alters the aggregating properties

For example:
• Aggregates more quickly (shortened lag phase)
• Reaches a high level of aggregation

40
Q

What is the function of tyrosine hydroxylase?

What is the significance?

A

Enzyme for synthesis of dopamine

In transgenic mice that were over-experssing α-synuclein:
• Reduced levels of this enzyme
→ Reduced dopamine

41
Q

Describe the propagation of recombinant α-synuclein

A

Recombinant :
from bacteria, i.e. has never been in a brain before

When the recombinant α-synuclein was injected into asymptomatic, non-transgenic mice it spread to other regions

42
Q

Describe the change in life span observed in mice injected with mutant α-synuclein brain lysate

A

Injected mice: die at around 280 days
• If injected very early (at birth) there is even sooner onset of death

Non-injected mice: around 470 days

Injection of the brain lysate reduces the life span of the transgenic mice

43
Q

In homozygous Parkin mutation, what is the age of onset of PD?

A

10-50 years: i.e. juvenile PD

44
Q

What is the age of onset of sporadic PD?

A

70-80 years

Later than the familial causes

45
Q

Describe the role of glucoscerebroside in PD

A

Glucoscerebroside stabilises α-synuclein oligomers

Normally it is broken down into ceremide in lysosomes

Mutations in the protein that break down glucoscerebroside lead to increased α-synuclein aggregation

46
Q

What factors intracellularly can lead to α-synuclein aggregation?

A
  • Parkin: decreased protein degradation
  • LRRK2: Golgi fragmentation
  • Glucoscerebroside: stabilisation of α-synuclein oligomers
  • LRRK2: Mitochondria fragmentation → energy loss from cells

BIOM30002 - M2M (36 decks)

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